EVIDENCE AGAINST AN EFFECT OF ENDOTHELIN-1 ON BLOOD-COAGULATION, FIBRINOLYSIS, AND ENDOTHELIAL-CELL INTEGRITY IN HEALTHY-MEN

On the basis of an array of preclinical experimental results, it has b een widely assumed that endothelin-1 (ET-1) may affect blood coagulati on, fibrinolysis, and endothelial cell function, thereby playing a pat hophysiological role in various cardiovascular diseases in humans. How ever, confirmation of this assumption is still lacking. ET-1 or placeb o was administered intravenously to 12 healthy volunteers in a prospec tive, randomized, double-blind, crossover trial. Pathophysiologically relevant concentrations of ET-1 (an approximate threefold increase of normal blood levels) causing hemodynamic effects were reached by conti nuous intravenous infusion for 6 hours. Components of the coagulation (thrombin-antithrombin complexes, prothrombin fragment F1+2, activated factor VII, and factor VII antigen) and fibrinolytic (fibrin split pr oduct D-dimer, plasmin-plasmin inhibitor complex, tissue-type plasmino gen activator, urokinase-type plasminogen activator, and plasminogen a ctivator inhibitor-1) systems and markers of endothelial cell perturba tion/dysfunction (von Willebrand factor and thrombomodulin) were measu red before the start of infusion and after 2, 6, 12, and 24 hours. Com paring changes in the plasma concentrations of these parameters during and after infusion of ET-1 and placebo, we found no specific effects of ET-1. In contrast to previous reports from preclinical experiments, ET-1 does not appear to affect coagulation or fibrinolysis, nor does this peptide induce relevant endothelial cell perturbations in humans.